Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes

Boughton, Charlotte K. Ph.D.
Allen, Janet M. R.N.
Ware, Julia M.D.
Wilinska, Malgorzata E. Ph.D.
Hartnell, Sara B.Sc.
Thankamony, Ajay M.Phil.
Randell, Tabitha M.D.
Ghatak, Atrayee M.D.
Besser, Rachel E.J. Ph.D.
Elleri, Daniela Ph.D.
Trevelyan, Nicola M.D.
Campbell, Fiona M. M.D.
Sibayan, Judy M.P.H.
Calhoun, Peter Ph.D.
Bailey, Ryan M.S.
Dunseath, Gareth Ph.D.
Hovorka, Roman Ph.D.

From the Wellcome-Medical Research Council Institute of Metabolic Science (C.K.B., J.M.A., J.W., M.E.W., R.H.) and the Department of Paediatrics (J.M.A., J.W., M.E.W., A.T., R.H.), University of Cambridge, and Wolfson Diabetes and Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust (C.K.B., S.H.), Cambridge, the Department of Paediatric Diabetes and Endocrinology, Nottingham Children's Hospital, Nottingham (T.R.), the Department of Diabetes, Alder Hey Children's NHS Foundation Trust, Liverpool (A.G.), the Department of Paediatrics, University of Oxford, and the National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford (R.E.J.B.), the Department of Diabetes, Royal Hospital for Sick Children, Edinburgh (D.E.), the Department of Paediatric Diabetes, Southampton Children's Hospital, Southampton (N.T.), the Department of Paediatric Diabetes, Leeds Children's Hospital, Leeds (F.M.C.), and the Diabetes Research Group, Swansea University, Swansea (G.D.) — all in the United Kingdom; and Jaeb Center for Health Research, Tampa, FL (J.S., P.C., R.B.).

Dr. Hovorka can be contacted at [email protected] or at the Wellcome-Medical Research Council Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Rd., Cambridge CB2 0QQ, United Kingdom.

^*The members of the CLOuD Consortium are listed in the Supplementary Appendix, available at NEJM.org.

Supported by the National Institute for Health and Care Research (NIHR ) Efficacy and Mechanism Evaluation Programme (14/23/09), the Helmsley Charitable Trust (2016PG-T1D045 and 2016PG-T1D046), and JDRF (22-2013-266 and 2-RSC-2019-828-M-N). Additional support for the artificial pancreas work was provided by the NIHR Cambridge Biomedical Research Centre and the NIHR Oxford Biomedical Research Centre.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The views expressed are those of the authors and not necessarily those of the funders.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

New England Journal of Medicine 387(10):p 882-893, September 8, 2022. | DOI: 10.1056/NEJMoa2203496

ABSTRACT

BACKGROUND

Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear.

METHODS

In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis.

RESULTS

A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, −0.06 pmol per milliliter [95% confidence interval {CI}, −0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, −0.04 pmol per milliliter [95% CI, −0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group.

CONCLUSIONS

In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.)